Stimulation of adenosine receptors in the nucleus accumbens reverses the expression of cocaine sensitization and cross-sensitization to dopamine D2 receptors in rats

Abstract

Adenosine receptors co-localize with dopamine receptors on medium spiny nucleus accumbens (NAc) neurons where they antagonize dopamine receptor activity. It remains unclear whether adenosine receptor stimulation in the NAc restores cocaine-induced enhancements in dopamine receptor sensitivity. The goal of these studies was to determine whether stimulating A(1) or A(2A) receptors in the NAc reduces the expression of cocaine sensitization. Rats were sensitized with 7 daily treatments of cocaine (15 mg/kg, i.p.). Following one-week withdrawal, the effects of intra-NAc microinjections of the adenosine kinase inhibitor (ABT-702), the adenosine deaminase inhibitor (deoxycoformycin; DCF), the specific A(1) receptor agonist (CPA) and the specific A(2A) receptor agonist (CGS 21680) were tested on the behavioral expression of cocaine sensitization. The results indicate that intra-NAc pretreatment of ABT-702 and DCF dose-dependently blocked the expression of cocaine sensitization while having no effects on acute cocaine sensitivity, suggesting that upregulation of endogenous adenosine in the accumbens is sufficient to non-selectively stimulate adenosine receptors and reverse the expression of cocaine sensitization. Intra-NAc treatment of CPA significantly inhibited the expression of cocaine sensitization, which was reversed by both A(1) and A(2A) receptor antagonism. Intra-NAc treatment of CGS 21680 also significantly inhibited the expression of cocaine sensitization, which was selectively reversed by A(2A), but not A(1), receptor antagonism. Finally, CGS 21680 also inhibited the expression of quinpirole cross-sensitization. Together, these findings suggest that adenosine receptor stimulation in the NAc is sufficient to reverse the behavioral expression of cocaine sensitization and that A(2A) receptors blunt cocaine-induced sensitization of postsynaptic D(2) receptors.

Figure 1. Intra-NAc administration of adenosine kinase and adenosine deaminase inhibitors attenuates the expression of cocaine sensitization

(a) Animals repeatedly treated with cocaine (7 X 15 mg/kg, ip) displayed significant expression of sensitization when tested with intra-NAc vehicle and 15 mg/kg cocaine (ip) following 7 days withdrawal compared with animals administered repeated saline. Intra-NAc administration of both the adenosine kinase inhibitor (ABT-702) and adenosine deaminase inhibitor (DCF) diminished the expression of cocaine sensitization. No effect of intra-NAc ABT-702 or DCF was observed on acute cocaine sensitivity since cocaine-induced locomotor activity was equivalent in cocaine-naïve animals. (b) Time-course of locomotor activity illustrating the last 30 min of the habituation period followed by the effects of 15 mg/kg cocaine (ip) with and without the intra-NAc pretreatment ABT-702 (5 µg/side) or DCF (10 µg/side) in cocaine-sensitized animals. * indicates significant from cocaine-naïve with vehicle pretreatment (p<0.0001); # indicates significant from cocaine-sensitized with vehicle pretreatment (p<0.01)

Figure 2. Effects of intra-NAc administration adenosine kinase and adenosine deaminase inhibition in cocaine-sensitized and cocaine-naïve

(a) An intra-NAc treatment with the adenosine kinase inhibitor, ABT-702, had no effect on locomotion in either cocaine-sensitized or cocaine-naive animals. (b) An intra-NAc treatment with the adenosine deaminase inhibitor, DCF, had no effect on locomotion in either cocaine-sensitized or cocaine-naive animals.

Figure 3. Intra-NAc administration of adenosine receptor agonists attenuates the expression of cocaine sensitization

(a) Animals repeatedly treated with cocaine (7 × 15 mg/kg, ip) displayed significant expression of sensitization when tested with intra-NAc vehicle and 15 mg/kg cocaine (ip) following 7 days withdrawal compared with animals administered repeated saline. Intra-NAc administration of both the adenosine A_2A agonist (CGS 21680) and adenosine A₁ agonist (CPA) diminished the expression of cocaine sensitization. No effect of intra-NAc CGS 21680 or CPA was observed on acute cocaine sensitivity since cocaine-induced locomotor activity was equivalent in cocaine-naïve animals. (b) Time-course of locomotor activity illustrating the last 30 min of the habituation period followed by the effects of 15 mg/kg cocaine (ip) with and without the intra-NAc pretreatment CGS 21680 (5 µg/side) or CPA (1.5 µg/side) in cocaine-sensitized animals. * indicates significant from respective cocaine-naïve group (p<0.0001); # indicates significant from cocaine-sensitized with vehicle pretreatment (p<0.001)

Figure 4. Effects of intra-NAc treatment of A₁ and A_2A antagonists in cocaine-naïve and cocaine-sensitized animals

Animals sensitized to cocaine with 7 daily cocaine injections (15 mg/kg, ip) displayed modest increases in locomotor activity compared to cocaine-naïve (saline treated) animals. * indicates significant from respective cocaine-sensitized, vehicle group (p<0.05)

Figure 5. Effects of intra-NAc treatment of A₁ and A_2A on adenosine agonist-induced inhibition of cocaine sensitization

Animals were sensitized to cocaine with 7 daily cocaine injections (15 mg/kg, ip). As reported above, CPA and CGS alone significantly reduced the expression of cocaine sensitization (left). Intra-NAc pretreatment of the A₁ antagonist, DPCPX (middle), reversed CPA-induced reductions in cocaine sensitization, but not CGS 21680-induced reductions. Intra-NAc pretreatment of the A_2A antagonist, MSX-3 (right), significantly reversed CGS 21680-induced and CPA-induced reductions in the expression of cocaine sensitization. * indicates significant from vehicle-vehicle group (p<0.01); # indicates significant from respective agonist-vehicle group (p<0.05)

Figure 6. Intra-NAc treatment of an A_2A receptor agonist reduces locomotor sensitivity of the D₂ agonist in both cocaine-naïve and cocaine-sensitized

Locomotor activity induced by a high dose of the D₂ receptor agonist, quinpirole (0.3 mg/kg, sc) is attenuated in both cocaine-naïve and cocaine-sensitized animals. Importantly, cocaine-sensitized animals displayed crosssensitization in D₂-induced locomotion, which was attenuated to levels similar to cocaine-naïve animals. * indicates significant from vehicle treated cocaine-naïve group (p<0.0001); # indicates significant from cocaine-sensitized with vehicle pretreatment (p<0.001)

Figure 7. Localization of infusion sites in NAc core

(a) Some infusion sites were verified by an infusion of 1.0 µL/side of 0.1% cresyl violet through the guide cannula following euthanasia and 40 µm sections were analyzed for accurate placements. (b)Infusion sites were also verified by staining non-infused 40 µm brain sections with cresyl violet. There were minimal signs of gliosis or scarring following the intra-NAc infusions. (c) Infusion sites for all animals included in the study analyses. Animals having infusion sites outside of the NAc core were eliminated from statistical analyses.